Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen and they acquired their name because of their propensity to kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. Surprisingly little is known about receptors that activate the cytotoxic response of NK cells. A major goal of this project is to define the molecular basis of NK cell activation and to characterize the receptors involved. In addition, an in vivo model in mice has been developed to determine how activation and inhibition of NK cells and mast cells are controlled during exposure to various pathogens. A molecule called linker for activation of T cells (LAT) has been proposed to be essential for activation of NK cells. To address this possibility, NK cells from mice deficient in LAT were analyzed and shown to be fully functional in terms in cellular cytotoxicity. Thus, LAT is not required for activation of NK killing activity. Mice deficient in the genes encoding the molecules called gp49A and gp49B have been generated. The gp49B receptor has an inhibitory activity in both NK cells and mast cells. Such gp49- deficient mice have been bred for several generations with a congenic strain of mice in order to obtain a fairly pure genetic background. Once backcrossing is completed, such mice will be tested for their ability to respond to various infectious agents, in particular those known to elicit NK or mast cell responses. A unique receptor specific for the MHC class I molecule HLA-G has been characterized on human NK cells. Although it belongs to the family of killer cell immunoglobulin- like receptors (KIR) this receptor has several unique structural and functional characteristics. As HLA-G is expressed only on cytotrophoblast cells from the fetus, the HLA-G-specific receptor most likely delivers signals to maternal NK cells that contact fetal cytotrophoblast cells at the site of implantation during early pregnancy. - Activation signal, cytotoxicity, HLA-G, human leukocyte antigen (HLA), implantation, mast cell, natural killer (NK) cell, pregnancy